Droperidol

Droperidol’s inhibitory action on dopaminergic receptors in the chemotrigger zone in the area postrema, gives it a potent antiemetic effect, especially useful for the prevention and treatment of postoperative nausea and vomiting and/or nausea and vomiting induced by opioid analgesics.

Droperidol is a butyrophenone neuroleptic. Its pharmacologic profile is characterised mainly by dopamine-blocking and weak α1-adrenolytic effects. Droperidol is devoid of anticholinergic and antihistaminic activity.

At a dose of 0.15 mg/kg, droperidol induces a fall in mean blood pressure (MBP), due to a decrease in cardiac output in a first phase, and then subsequently due to a decrease in pre-load. These changes occur independently of any alteration in myocardial contractility or vascular resistance. Droperidol does not affect myocardial contractility or heart rate, therefore has no negative inotropic effect. Its weak α1-adrenergic blockade can cause a modest hypotension and decreased peripheral vascular resistance and may decrease pulmonary arterial pressure (particularly if it is abnormally high). It may also reduce the incidence of epinephrine-induced arrhythmia, but it does not prevent other forms of cardiac arrhythmia.

Droperidol has a specific antiarrhythmic effect at a dose of 0.2 mg/kg by an effect on myocardial contractility (prolongation of the refractory period) and a decrease in blood pressure.

The action of a single intravenous dose commences 2-3 minutes following administration. The tranquillising and sedative effects tend to persist for 2 to 4 hours, although alertness may be affected for up to 12 hours.

Distribution

Following intravenous administration, plasma concentrations fall rapidly during the first 15 minutes; this is metabolism independent, redistribution of the drug. Plasma protein binding amounts to 85-90%. The distribution volume is approximately 1.5 l/kg.

Metabolism

Droperidol is extensively metabolised in the liver, and undergoes oxidation, dealkylation, demethylation and hydroxylation by cytochrome P450 isoenzymes 1A2 and 3A4, and to a lesser extent by 2C19. The metabolites are devoid of neuroleptic activity.

Elimination

Elimination occurs mainly through metabolism; 75% is excreted via the kidneys. Only 1% of the active substance is excreted unchanged with urine, and 11% with faeces. Plasma clearance is 0.8 (0.4-1.8) l/min. The elimination half-life (t½ß) is 134 ± 13 min.

Paediatric Population

In a study of 12 children (age 3.5 to 12 years), the values for distribution volume and clearance reported were lower than those found in the adult population (0.58 ± 0.29 l/kg and 4.66 ± 2.28 ml/kg*min respectively) and decrease in parallel. The elimination half-life (101.5 ± 26.4 min) was similar to that found in adults.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxic or carcinogenic potential, and reproductive toxicity.

Electrophysiological in vitro and in vivo studies indicate an overall risk of droperidol to prolong the QT interval in humans.

In humans, the free peak plasma concentration is approximately 4-fold higher to 25-fold lower than the droperidol concentrations affecting the endpoints examined in the different in vitro and in vivo test systems used to assess the impact of this drug on cardiac repolarisation. Plasma levels fall by about one order of magnitude over the first twenty minutes after administration.

Environmental Risk Assessment (ERA)

This product is unlikely to represent a risk to the environment following its prescribed use in patients.